Room 1768 WIMR
Department of Pathology & Lab Medicine
1111 Highland Avenue
Madison, WI 53705
- (608) 265-7000 #3595
- 1768 WIMR
Hematopoietic development from pluripotent stem cells; de novo generation of hematopoietic stem cells
Hematopoietic stem cell transplantation has become the standard of care for treatment of many otherwise incurable diseases such as leukemia, lymphoma and multiple myeloma. In addition, hematopoietic stem cell transplantation is used for treatment of hereditary disorders such as anemia (sickle-cell anemia, beta-thalassemia, and aplastic anemia), inborn errors of metabolism, immunodeficiencies, and autoimmune diseases. However, insufficient numbers of hematopoietic stem cells, graft failure, inadequate anti-tumor immune response after transplantation, and graft-versus- host disease remain significant limitations to the success of hematopoietic stem cell transplantation. The main focus of research in my lab is to significantly advance the clinical use of stem cells through development of novel sources of hematopoietic stem cells and mature blood cells for transplantation, transfusion and cancer immunotherapy.
We focused on the following strategies to generate alternative sources of therapeutic blood cells:
Directed differentiation of human embryonic stem (hES) cells and induced pluripotent stem (iPS) cells into the hematopoietic stem and mature blood cells.
Reprogramming of pluripotent stem cells and non-hematopoietic somatic cells into the blood cells.
Using these methodologies, we anticipate generating immunologically compatible hematopoietic stem and immunotherapeutic cells in large quantities. In this way we can eliminate serious complications of bone marrow transplantation such as graft-versus-host disease and transplant failure, and at the same time generate a significant anti-tumor immune response.
We use integrative approaches, including genomics, proteomics and bioinformatics, to achieve the outlined goals and to understand important cellular, and molecular events leading to blood cell development and diversification. We already developed a very efficient system for hematopoietic and endothelial differentiation of hES and iPS cells, and directed differentiation of hES cells toward red blood cells, dendritic cells, macrophages, osteoclasts, and granulocytes. In addition, we defined the major cellular pathways leading to formation of blood cells and identified several novel hematoendothelial, hematopoietic and mesenchymal progenitors. Through comparative analysis of transcriptome and engraftment properties of these novel progenitors and fetal primitive blood cells as well as employing loss-of- and gain-on-function and lienage-tracing experiments, we expect to gain fundamental insights into molecular mechanisms leading to blood cell development. These studies could ultimately revolutionize cellular therapies for blood cancer and hereditary blood disease, and can be exploited for discovery of new drugs regulating hematopoietic stem cells, as well.
General Surgical Pathology, Gastrointestinal tract pathology
- NOTCH Activation at the Hematovascular Mesoderm Stage Facilitates Efficient Generation of T Cells with High Proliferation Potential from Human Pluripotent Stem Cells. Kumar A, Lee JH, Suknuntha K, D’Souza SS, Thakur AS, Slukvin II. J Immunol. 2019 Feb 1;202(3):770-776. doi: 10.4049/jimmunol.1801027. Epub 2018 Dec 21. PMID:30578305
- McIntosh BE, Brown ME, Duffin BM, et al. “Nonirradiated NOD,B6.SCID Il2rγ-/- Kit(W41/W41) (NBSGW) mice support multilineage engraftment of human hematopoietic cells.” Stem Cell Reports. 2015;4(2):171-80.
- D’Souza SS, Maufort J, Kumar A, et al. “GSK3β Inhibition Promotes Efficient Myeloid and Lymphoid Hematopoiesis from Non-human Primate-Induced Pluripotent Stem Cells.” Stem Cell Reports. 2016;6(2):243-56.
- Hafner A-L, Contet J, Ravaud C, et al. “Brown-like adipose progenitors derived from human induced pluripotent stem cells: Identification of critical pathways governing their adipogenic capacity.” Sci Rep. 2016;6:32490.